Expert Critique

Considering how novel the data are about use of checkpoint blockade in the management of advanced melanoma, as well as in other malignancies, it is not surprising that there is as yet no specific guideline in regards to the appropriate timing and sequencing of these agents. This article proves to be relevant and succinct, at least in the melanoma arena, where we are getting more mature information.

Definitely patients' performance status is important but so is the availability of resources (cost-effectiveness, scheduling, and personnel), and this concise Q&A with two experts will help further streamline decision-making in this population.

As long as patients are able to tolerate the expected side effects, which are more frequently observed when combining CTLA-4 and PD-1 blockade, the recommendations from this small article are something to discuss when talking about treatment with patients, and indicate a future paradigm shift in the use of checkpoint blockade not only in BRAF-negative melanoma but also in other solid malignancies in which a benefit of checkpoint blockade has already been observed.

Full Critique

Combination immunotherapy with a programmed death (PD)-1 inhibitor, such as nivolumab or pembrolizumab, plus the cytotoxic T-lymphocyte-associated protein 4 inhibitor ipilimumab is now considered the best choice for first-line systemic therapy for BRAF-negative advanced melanoma.

For the approximately half of advanced melanoma patients who lack BRAF mutations in tumors, immunotherapy with checkpoint inhibitors has become the standard first-line systemic therapy. The cytotoxic T-lymphocyte-associated protein 4 inhibitor ipilimumab was the first of the checkpoint inhibitors to be approved by the FDA. Now the PD-1 inhibitors nivolumab and pembrolizumab have also been approved, and data suggest that a combination of nivolumab plus ipilimumab may be a better choice for first-line therapy in these advanced melanoma patients.

Two melanoma experts, Michael Atkins, MD, of the Georgetown University School of Medicine, and Jeffrey Weber, MD, PhD, of NYU Langone Medical Center, provide insights into how they decide which first-line immunotherapy to prescribe for their patients with advanced melanoma without BRAF mutations.

What is the preferred first-line systemic therapy for advanced BRAF-negative melanoma?

Atkins: I think it is nivolumab plus ipilimumab in all patients who can tolerate it. I would define this as people age 80 or under with decent organ function and a performance status of 0 or 1. In other patients, the treatment of choice is pembrolizumab or nivolumab.

What drives the decision process for the choice of first-line systemic therapy?

Atkins: The choice between pembrolizumab or nivolumab is related primarily to schedule. Pembrolizumab is given once every 3 weeks and nivolumab, once every 2 weeks.

Weber: BRAF mutation status, bulk of disease, and the rate of tumor growth are the parameters we use to decide what to give as first-line therapy. In addition, performance status and physiologic age will come into play.

How do the results of the CheckMate-064 trial influence the decision? (This Phase II study found that twice as many patients responded to sequential administration of nivolumab followed by ipilimumab -- 41% -- as compared with ipilimumab followed by nivolumab -- 20%.)

Weber: It would suggest that PD-1 blockade would be a better first choice than ipilimumab, especially if there would be a rapid switch from one to the other in the case of progression.

Atkins: To me the results suggest that you should give your best treatment first. This means that nivolumab plus ipilimumab should be given to all those who can tolerate it.

How do you see ipilimumab incorporated into treatment?

Weber: As an element of a combination regimen with nivolumab or pembrolizumab, and as a second-line therapy alone or in novel combinations in patients who have failed to respond to front-line PD-1 blockade.

Atkins: Eventually, the dose of ipilimumab will be decreased or the schedule truncated, but we need to validate that efficacy is not lost.

What data suggest long-term benefits of the immune checkpoint antibodies?

Atkins: Mario Sznol, MD, presented data (as yet unpublished) at the Society of Melanoma Research (SMR) meeting that show 30-40% four-survival for patients taking nivolumab. The Keynote 001 study is showing median survival of around 22.2 months for pembrolizumab, and 60% of treatment-naïve patients are alive at 2 years with long response durations. F. Stephen Hodi, MD, presented data at the SMR meeting (also as yet unpublished) suggesting that nivolumab plus ipilimumab will lead to 2-year survival in the 70-80% range. Data with longer follow-up should be emerging soon for all of these regimens.

Weber: A study led by Dirk Schadendorf, MD, in the Journal of Clinical Oncology last year showed a 20% plateau for ipilimumab patients after 3 years of survival and the longest follow-up with pembrolizumab and nivolumab data, suggesting a 30% tail on the overall survival curve.

What is the bottom-line message for practicing oncologists?

Atkins: Ipilimumab should no longer be considered a first-line therapy for patients with advanced melanoma. Combination immunotherapy adds more than single-agent anti-PD-1 and should be given to all who can tolerate it. There is still a lot of research to be done to determine the optimal combinations, optimal doses, and schedules; which patients should be treated; and how these regimens should be integrated with standard therapies.

Weber: Decide carefully in both BRAF wild-type or mutated patients whether to use ipilimumab plus nivolumab or a PD-1 drug alone front-line, and if the latter, follow with ipilimumab.

Accessibility Statement

At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email.